Small molecule inhibition of sulfotransferase SULT1A3

Abstract

Provided herein are small molecule compounds and methods inhibiting human sulfotransferase 1A3 (SULT1A3) using these small molecule compounds. Methods of manufacturing and treatment are also disclosed.

The invention claimed is: 
     
       1. A compound having the structure of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
       
       
         
           
           
               
               
           
         
       
       is a naphthalene or a quinoline;
 X is selected from a bond and an optionally substituted alkyl or alkene; 
 Y is selected from —OR′, —CONR′ 2 , —COOR′ and optionally substituted heteroaryl; 
 R′ is H or an optionally substituted alkyl; 
 Z is independently selected from H, optionally substituted alkyl, and —X-Y, or two Z together form an optionally substituted cycloalkyl, wherein when Z 1  and Z 2  are both H, then Y is heteroaryl, or wherein Z 1  and Z 2  are not both H; 
 a is 0 or an integer of 1-4; and 
 wherein the compound of formula (I) is selected from: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       2. A compound having the structure of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from a —C 0 -C 6  alkyl or a —C 2 -C 6  alkene; 
 Y is selected from —OR', —COOR′, —CONR′ 2 , and heteroaryl; 
 R′ is H or C 1 -C 6  alkyl; 
 Z 1  is selected from H and —OR′; and 
 Z 2  is selected from H, —C 1 -C 6  alkyl, and —C 0 -C 6 -COOR′, or 
 Z 1  and Z 2  together form a substituted cycloalkyl, 
 wherein when Z 1  and Z 2  are both H, then Y is heteroaryl and 
 wherein the compound of formula (II) is selected from: 
 
       
       
         
           
           
               
               
           
         
       
     
     
       3. A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
       4. A method of inhibiting SULT1A3 in a subject in need thereof, comprising administering a compound of  claim 1 , or a composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier to the subject. 
     
     
       5. The method of  claim 4 , wherein the subject is a human. 
     
     
       6. A method inhibiting SULT1A3 in a cell, comprising contacting a cell with a compound of  claim 1 . 
     
     
       7. The method of  claim 6 , wherein the cell is a mammalian cell, and optionally wherein the mammalian cell is a human cell. 
     
     
       8. A method of inhibiting the activity of SULT1A3, comprising providing a SULT1A3 enzyme, and contacting the SULT1A3 enzyme with a compound of  claim 1 . 
     
     
       9. The method of  claim 8 , wherein:
 (a) the contacting of SULT1A3 is performed in vitro; or 
 (b) the contacting of SULT1A3 is performed in vivo. 
 
     
     
       10. A method of prolonging therapeutic efficacy of a catecholic drug or lowering the effective concentration of a catecholic drug in a subject in need, comprising administering a compound of  claim 1 , or a composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier, to the subject. 
     
     
       11. A method of preventing metabolization of dopamine in a subject in need comprising administering a compound of  claim 1 , or a composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier, to the subject. 
     
     
       12. A method of retarding tumor progression of hepatocellular carcinoma in a subject in need comprising administering a compound of  claim 1 , or a composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier, to the subject.